title: Leu452His mutation in lipoprotein lipase gene transfer associated with hypertriglyceridemia in mice in vivo.
abstract: Mutated mouse lipoprotein lipase (LPL) containing a leucine (L) to histidine (H) substitution at position 452 was transferred into mouse liver by hydrodynamics-based gene delivery (HD). Mutated-LPL (MLPL) gene transfer significantly increased the concentrations of plasma MLPL and triglyceride (TG) but significantly decreased the activity of plasma LPL. Moreover, the gene transfer caused adiposis hepatica and significantly increased TG content in mouse liver. To understand the effects of MLPL gene transfer on energy metabolism, we investigated the expression of key functional genes related to energy metabolism in the liver, epididymal fat, and leg muscles. The mRNA contents of hormone-sensitive lipase (HSL), adipose triglyceride lipase (ATGL), fatty acid-binding protein (FABP), and uncoupling protein (UCP) were found to be significantly reduced. Furthermore, we investigated the mechanism by which MLPL gene transfer affected fat deposition in the liver, fat tissue, and muscle. The gene expression and protein levels of forkhead Box O3 (FOXO3), AMP-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) were found to be remarkably decreased in the liver, fat and muscle. These results suggest that the Leu452His mutation caused LPL dysfunction and gene transfer of MLPL in vivo produced resistance to the AMPK/PGC-1α signaling pathway in mice.
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Kaiyue
authors.initials: K
authors.lastname: Sun
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.forename: Yanna
authors.initials: Y
authors.lastname: Huang
authors.forename: Yizhen
authors.initials: Y
authors.lastname: Wang
authors.forename: Lan
authors.initials: L
authors.lastname: Xiang
authors.forename: Jianhua
authors.initials: J
authors.lastname: Qi
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D017931:DNA Primers / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D015228:Hypertriglyceridemia / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018482:Muscle, Skeletal / Q000378:metabolism; D020125:Mutation, Missense / Q000235:genetics*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D017931:DNA Primers; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D055372:AMP-Activated Protein Kinases; D008071:Lipoprotein Lipase